Bullous pemphigoid (BP) is a prototypical organ-specific autoimmune disease. Autoantibodies unfold their blister-inducing potential by triggering an Fcγ-dependent inflammatory reaction. The study by Iwata et al. in this issue provides the first direct evidence that IgG autoantibodies from BP patients may also weaken cell–matrix adhesion by depleting BP180/type XVII collagen from cultured keratinocytes. These novel findings shed new light on additional mechanisms of blister formation in pemphigoid diseases and open the way for further informative studies.

Bullous pemphigoid (BP) is a subepidermal blistering disease that typically affects the elderly and is associated with an autoimmune response against hemidesmosomal proteins (Liu and Diaz, 2001; Mihai and Sitaru, 2007; Olasz and Yancey, 2008). Extensive clinical and experimental evidence strongly suggests that autoantibodies cause the pathology in this disease (Sitaru and Zillikens, 2005; Leighty et al., 2007). Circulating autoantibodies in BP patients exhibit a heterogeneous specificity to several hemidesmosomal components, including BP230, an intracellular constituent of the hemidesmosomal plaque, and the transmembrane protein BP180/type XVII collagen (Sitaru and Zillikens, 2005; Leighty et al, 2007). Mutations in COL17A1 in patients with generalized atrophic benign epidermolysis bullosa and in knockout mice result in low or absent expression of BP180/type XVII collagen and subepidermal blistering (McGrath et al., 1995; Nishie et al., 2007). These findings suggest that a decrease in the expression of this hemidesmosomal antigen may weaken cell–matrix adhesion in the skin and eventually result in dermal–epidermal separation.

Autoantibodies to the transmembrane antigen BP180, but not to the intracellularly located BP230, were hypothesized to be pathogenically relevant (Liu and Diaz, 2001; Sitaru and Zillikens, 2005). Indeed, experimental evidence generally supports the pathogenic role of autoantibodies to BP180 for blister formation. IgG autoantibodies, affinity purified against recombinant BP180 from patients with BP and pemphigoid gestationis, induce dermal–epidermal separation in cryosections of human skin when co-incubated with leukocytes from healthy donors (Sitaru and Zillikens, 2005). In 1993, Liu et al. first provided evidence for a pathogenic role of autoantibodies to type XVII collagen/BP180 in vivo (Liu et al., 1993). The authors demonstrated that rabbit antibodies generated against murine BP180 induce subepidermal blisters when passively transferred into neonatal mice. More recently, further animal models reproducing blister formation in BP have been developed using mice that express the human form of the BP180 antigen injected with BP patient autoantibodies. Studies performed mainly with the experimental model developed by Liu et al. (1993) revealed that subepidermal blistering triggered by rabbit IgG specific to murine BP180 depends on complement activation, mast cell degranulation, macrophage activation, and neutrophilic infiltration. Reactive oxygen species and proteases, such as gelatinase B/MMP-9 and elastase, are critically involved in blister formation

IgG autoantibodies deplete BP180 from keratinocytes.

in vivo and in vitro (Liu and Diaz, 2001; Liu, 2004; Sitaru and Zillikens, 2005; Leighty et al., 2007). These findings partially match the pathology observed in BP patients and support the prevailing view that triggering an Fcγ-dependent inflammatory reaction is necessary for blister induction by autoantibodies in BP (Figure 1).Figure 1.Figure 1 – Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

Mechanisms of blister formation in bullous pemphigoid (BP). The left lower panel illustrates several structural proteins of the epidermal basement membrane that function as major autoantigens in autoimmune subepidermal bullous skin diseases. The main autoantigens in BP patients include the BP antigen 230 (BP230) and the BP antigen 180 (BP180)/type XVII collagen. BP autoantibodies accumulate in tissue and bind to antigens at the epithelial basement membrane. Binding of pathogenic autoantibodies triggers an inflammatory reaction, including fixation of complement and Fc-dependent activation of leukocytes. In addition to granulocytes, mast cells likely contribute to the antibody-induced inflammation at the dermal–epidermal junction. Activated granulocytes release reactive oxygen intermediates and proteases, leading to epithelial damage and blister formation. Alternatively, as shown by Iwata et al. (2009), IgG autoantibodies may deplete BP180 from basal keratinocytes and thus contribute to blister formation. LN 332, laminin 332; ROS, reactive oxygen species.Full figure and legend (158K)

Although the description of the relatively uncommon variant of BP with a paucicellular dermal infiltrate suggested the existence of alternative noninflammatory mechanisms of blister formation, until now experimental data did not support this hypothesis. A further hint that a full inflammatory response may not be required for subepidermal blistering by autoantibodies against BP180/type XVII collagen was provided by Yamamoto et al. (2002). They demonstrated that rabbit antibodies generated against hamster BP180 induced subepidermal blisters when passively transferred into neonatal hamsters. The blister formation in this model necessitates complement activation, but not the recruitment and activation of leukocytes (Yamamoto et al., 2002).

In this issue, Iwata et al. show that IgG autoantibodies from patients with BP deplete keratinocytes of BP180/type XVII collagen. When IgG from BP patients was added to cultured keratinocytes, the authors found that this treatment depleted BP180, but not α6β4 integrin, from cells as assessed by densitometric analysis of immunoblots. In addition, keratinocytes treated with IgG from BP patients showed a reduction in their adhesive strength as revealed by a standardized detachment assay (Iwata et al., 2009).

These findings describe new and potentially relevant mechanisms of blistering in BP and may have important consequences for the development of new treatment modalities. The fact that autoantibodies from patients with BP deplete BP180 from keratinocytes strongly suggests that alternative noninflammatory mechanisms contribute to blister formation in the pemphigoid diseases. Animal models of BP allow the in vivo relevance of these findings to be addressed and the relative contributions of the noninflammatory and inflammatory mechanisms of blister formation by autoantibodies to be dissected.

Autoantibodies in BP are thought to be heterogeneous with respect to their blister-inducing potential. Major intrinsic determinants of autoantibody pathogenicity include their specificity and their ability to activate complement and leukocytes (Sitaru and Zillikens, 2005). Future research should answer the question of whether the specificity of antigen-depleting autoantibodies differs when compared with that of autoantibodies that activate putative inflammatory mechanisms. BP autoantibodies belong to different isotypes, which may be associated with distinct effector functions. On the basis of previous experimental evidence, it has been proposed that blistering is induced primarily by IgG1, whereas IgG4 autoantibodies are less pathogenic or even protective (Liu, 2002; Sitaru et al., 2007). In light of the novel noninflammatory mechanisms of blister formation by autoantibodies as suggested by the study by Iwata et al. (2009), the role of different isotypes of autoantibodies in the pathogenesis of BP requires reappraisal.

In conclusion, this study strongly suggests the existence of noninflammatory mechanisms of blister formation by autoantibodies in BP. Further exploration of this line of research should provide relevant mechanistic insights into BP pathogenesis and greatly facilitate the development of more effective therapeutic approaches.

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The International Pemphigus & Pemphigoid Foundation’s most important objectives are to provide patients and doctors worldwide with information about pemphigus and pemphigoid, and to provide patients and their caregivers much needed comfort and support so they can continue to live active, productive lives.Read more »